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Clinical Nephrology, Vol. 74 – No. 1/2010 (19-24)

Seasonal variation of vitamin D in patients on hemodialysis R. Tolouian1, D.S. Rao2, M. Goggins2, S. Bhat2 and A. Gupta3

Original ©2010 Dustri-Verlag Dr. K. Feistle ISSN 0301-0430

1Division

of Nephrology and Hypertension, Texas Tech University Health Science Center at El Paso, TX, 2Divisions of Nephrology and Bone and Mineral Research Laboratory (D.S.R.), Henry Ford Hospital, Detroit, MI, and 3Rockwell Medical Technologies, Wixom, MI, USA Seasonal hypovitaminosis D in ESRD

Key words renal osteodystrophy – secondary hyperparathyroidism – vitamin D deficiency

Abstract. Background: Seasonal and racial differences in serum 25-hydroxyvitamin D levels have been studied extensively in the general population but not in patients with end-stage renal disease (ESRD). Methods: Serum 25-hydroxyvitamin D levels, the best available index of vitamin D nutrition, was measured at the end of summer (September) in 142 chronic hemodialysis patients and again at the end of winter (April) in 73 of these 142 patients, to determine the prevalence and risk factors for vitamin D deficiency. Results: The prevalence of vitamin D depletion, as defined by serum 25-hydroxyvitamin D level of less than 20 ng/ml (50 nmol/l), was 54% at the end of summer and further increased to 86% by the end of winter (p < 0.0001 summer vs. winter). We observed that women and African-Americans had a greater prevalence of hypovitaminosis D (p < 0.0002 and p < 0.001 for both comparisons, respectively). Surprisingly, diabetic status, age, and the duration of ESRD were not associated with a significant increase in risk of vitamin D depletion. Conclusion: Vitamin D depletion is present in about half of ESRD patients with marked seasonal variations. Patients with ESRD should have more frequent assessments of their vitamin D nutrition by serum 25-hydroxyvitamin D levels, and vitamin D supplementation should be routinely prescribed, which may prevent many of the complications related to vitamin D deficiency and secondary hyperparathyroidism.

Received May 4, 2009; accepted in revised form January 14, 2010

Introduction

Correspondence to A. Gupta, MB,BS, MD, Office of Chief Scientific Officer, Rockwell Medical 30142 S. Wixom Rood Wixom, MI 48393, USA agupta@ rockwellmed.com

Vitamin D deficiency is a risk factor not only for osteoporosis and bone fractures [1, 2, 3], but also for a variety of other non-skeletal conditions such as congestive heart failure [4], peripheral arterial disease [5], and hypertension [6]. The prevalence of vitamin D deficiency in residents of nursing homes and peo-

ple over the age of 65 is between 25% and 54% [7, 8, 9, 10, 11]. Vitamin D deficiency is present in about 50% of patients hospitalized on general medical service and uremia is an independent risk factor for vitamin D deficiency [12]. However, the prevalence of vitamin D deficiency in outpatient end-stage renal disease (ESRD) patients has not been determined. Previous studies have shown that after the administration of high doses of 25hydroxyvitamin D in uremic patients, the levels of the 1,25-dihydroxyvitamin D increases [13], which illustrates that the rise in the concentration of the precursor substance 25hydroxyvitamin D causes a rise in the concentration of the product substance 1,25-dihydroxyvitamin D. Previous studies have also shown that renal osteodystrophy can be treated with 25-hydroxyvitamin D replacement [14]. Since 1,25-dihydroxyvitamin D is both an endocrine substance and paracrine agonist, the benefits of correcting hypovitaminosis D extends beyond the mere increase in the circulating levels of 1,25-dihydroxyvitamin D. It is important to define the scope and magnitude of vitamin D deficiency in dialysis patients, since replacement of vitamin D is simple and avoidance of vitamin D depletion is associated with reduced incidence of fractures, morbidity and mortality [15].

Methods The purpose of this study was to determine the prevalence and risk factors for vitamin D deficiency. This was a retrospective study and exempt from IRB approval. We have assessed serum 25-hydroxyvitamin D levels, the best available index of vitamin D

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Table 1. Determinants of vitamin D deficiency in ESRD patients at the end of summer*. Variables

Serum 25-hydroxyvitamin D level (ng/ml) Patients n (%)

Sufficiency > 20 ng/ml

Patients (%)

142 (100%)

46%

48%

6%

Average age (range) (y)

64 (25 – 91)

63

65

60

Females

66 (46%)

30%

62%

8%

Males

76 (54%)

61%

34%

5%

Whites

74 (52%)

59%

33%

8%

African-Americans

68 (48%)

32%

64%

4%

Diabetic

39 (27%)

51%

41%

8%

Non-diabetic

103 (73%)

45%

49%

6%

1,650

1,716

1,639

833

Average duration of ESRD (days)

serum albumin [17]. Serum 25-(OH) D was measured by radioimmunoassay (INCSTAR Corp., Stillwater, MN, USA); reference range, 15 – 60 ng/ml (37.44 – 149.76 nmol/l).

Insufficiency Deficiency 10 – 20 ng/ml < 10 ng/ml

*The sum of the rows may not be 100 because the figures have been rounded. Note. To convert serum 25- hydroxyvitamin D in ng/ml to nmol/l, multiply by 2.496.

nutrition [16], in 142 patients on maintenance hemodialysis at the end of summer (September 1998) when vitamin D levels are expected to peak. In 73 of these 142 patients, serum 25-hydroxyvitamin D levels were again measured at the end of winter (April 1999) when levels are expected to reach the nadir. Of 142 patients, 54% and 52%were male and Caucasian, respectively (Table 1). None of these patients were on vitamin D supplements. Of the 142 patients, a subset of patients had vitamin D level measured at the end of winter. The latter cohort had not been selected for any particular characteristic. A single level was available in the rest due to a variety of reasons including loss to follow-up secondary to renal transplantation, transfer to another facility, death etc.

Definition of hypovitaminosis D For defining hypovitaminosis D, data from the previous studies were used [18, 19, 20]. Patients with serum 25-hydroxyvitamin D levels of 10 ng/ml were considered to have vitamin D deficiency, as these patients show biochemical and bone histomorphometric evidence of secondary hyperparathyroidism and/or mineralization defect. Patients with serum 25-hydroxyvitamin D levels of 10 – 20 ng/ml were considered to have vitamin D insufficiency. This is also associated with secondary hyperparathyroidism; which can be suppressed by supplemental vitamin D. Patients with serum 25-hydroxyvitamin D levels of 20 ng/ml do not have excess PTH secretion and vitamin D supplementation has no effect on the serum PTH level. This group of patients was considered vitamin D sufficient.

Statistical methods Associations between sex, race and diabetic status, and the outcome status (vitamin D sufficiency, insufficiency, or deficiency) were assessed for statistical significance using the c2-test or Fisher’s exact- test as appropriate. Mean age and mean days on dialysis by the outcome status were evaluated using a one-way analysis of variance; p values of 0.05 or less were considered statistically significant.

Results Laboratory studies Serum levels of total calcium (Ca; reference range, 8.2 – 10.0 mg/dl (2.05 – 2.46 mmol/l)), phosphate (P; reference range, 2.5 – 4.5 mg/dl (0.81 – 1.45 mmol/l)), creatinine (reference range, 0.6 – 1.5 mg/dl (53.04 – 132.6 mmol/l)), total protein, and albumin were measured in the hospital laboratory by standard methods using a Hitachi-747 autoanalyzer (Hitachi, Hialeah, FL, USA). Serum Ca was adjusted for

The characteristics of chronic hemodialysis patients (n =142) who participated in this study are as follows: The mean age of 142 patients was 64 years (range 25 – 91 years), average duration of ESRD was 4.5 years (range 0.47 – 28.1 years), and the study population included 54% males, 46% females, 48% African-Americans, 52% whites, 27% diabetics, and 73% non-diabetics (Table 1). We observed that women had a greater prevalence

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Seasonal hypovitaminosis D in ESRD

of hypovitaminosis D (70%) as compared to 39% in men (p< 0.0002). Race was another risk factor with a higher prevalence of vitamin D depletion in African-Americans (68%) compared to whites (41%). Diabetic status, age, or the duration of ESRD was not associated with a significant increase in risk of vitamin D depletion (Figure 1). The prevalence of hypovitaminosis D at the end of summer in 142 patients was 54% (n = 78) (Table 2). 6% of patients exhibited vitamin D deficiency while 48% had insufficiency. In a subgroup of 73 patients studied again at the end of winter, the prevalence of vitamin D deficiency and insufficiency increased to 86% (p < 0.0001) (Figure 2).

Discussion Figure 1. Prevalence of hypovitaminosis D (£ 20 ng/ml) by selected factors.

Figure 2. Seasonal variation in the prevalence of hypovitaminosis D (£ 20 ng/ml) in CKD Stage 5 patients.

Table 2. Seasonal variation in serum 25-hydroxyvitamin D levels and prevalence of hypovitaminosis D levels in ESRD patients. Season

Serum 25-hydroxyvitamin D (ng/ml) Mean ± SD

Sufficiency > 20 (ng/ml)

Insufficiency Deficiency 10 – 20 (ng/ml) < 10 (ng/ml)

End of summer (n = 142)

22 ± 12.8

46%

48%

6%

End of winter (n = 73)

15 ± 6.1

15%

67%

18%

Level of 25-hydroxyvitamin D level at the end of winter vs. summer, p < 0.0001. Note: to convert serum 25-hydroxyvitamin D in ng/ml to nmol/l, multiply by 2.496.

We found a very high prevalence of hypovitaminosis D in the Detroit ESRD population. As expected, a significantly higher prevalence of hypovitaminosis D was found at the end of the winter season. Seasonal variations in other laboratory measurements have been observed in chronic hemodialysis patients [21], but to our knowledge there are no reports of the seasonal variation in 25-hydroxyvitamin D levels in ESRD patients. ESRD patients uniformly have abnormally low concentrations of 1, 25-dihydroxyvitamin D and 24, 25-dihydroxyvitamin D, but the substrate availability (25-hydroxyvitamin D) is an important determinant of the circulating concentrations of these metabolites. Supplementation of 25-hydroxyvitamin D can increase circulating level of 1,25-dihydroxyvitamin D in the absence of renal tissue, indicating extrarenal production of 1,25-dihydroxyvitamin D [22]. Plasma 25-hydroxyvitamin D levels provide a direct and integrated assessment of vitamin D intake and stores because the serum half-life of 25hydroxyvitamin D is about 3 weeks [23]. Vitamin D stores are derived from dietary intake or cutaneous synthesis following exposure of skin to ultraviolet rays. In the United States, milk is a major source of vitamin D in the general population. However, dietary intake of milk and other dairy products is restricted in ESRD patients, because of the high phosphate content. Fish is another rich source of vitamin D. However, its high phosphate con-

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tent [24] (128 – 506 mg/100 g) limits its intake in ESRD patients. Anorexia secondary to uremia may contribute to malnutrition and associated vitamin D depletion. Since dietary intake of vitamin D may not be sufficient in uremic patients, cutaneous synthesis becomes an important source of vitamin D in the ESRD population. However, during the winter, at latitudes above 35 degrees North and South, very little, if any, vitamin D can be produced in the skin. For example, in Boston (42 °N) no significant vitamin D is produced from November through February even after 5 hours exposure to sun [25]. In Edmonton, Canada, and Bergen, Norway, vitamin D production is halted between the months of October and April [26]. ESRD is more common in older patients, and with increasing age there is a decline in skin synthesis and intestinal absorption of vitamin D [27, 28]. Therefore, age may be another factor contributing to the high prevalence of hypovitaminosis D in our study population, but we were not able to show this correlation in our study. In the nonuremic hyperparathyroid patients, the growth of parathyroid adenoma is related to 25-hydroxyvitamin D rather than to 1,25-dihydroxyvitamin D [29]. In addition to its known skeletal effects, vitamin D depletion has been associated with a variety of extraskeletal effects including increased risk of atherosclerosis [30], hypertension [6, 31], breast, colon, ovarian and prostate cancer [32, 33, 34, 35], autoimmune disorders [36] including Type 1 diabetes [37, 38, 39, 40], multiple sclerosis [41, 42, 43], impaired macrophage function [44] and increased risk of tuberculosis [45]. Atherosclerotic vascular and heart diseases, infections and diabetes are leading causes of morbidity and mortality in ESRD patients. Role of hypovitaminosis D in contributing to the above morbidities in ESRD patients remains to be studied. One may argue about the value of 25-(OH)D > 20 ng/ml which in our study was considered sufficient versus KDOQI guideline that defines sufficiency > 30 ng/ml. We recognize the potential inconsistency, but the inflection point of PTH on 25-(OH)D is actually at 20 ng/ml, not at 30 ng/ml; the latter was chosen as a “consensus” value. Indeed, there is no further decline in PTH after vitamin D therapy when the baseline level of 25-(OH)D is > 20 ng/ml [20]. In an earlier cross-sectional study of elderly

subjects, the PTH inflection point was at 15 ng/ml of 25-(OH)D, whereas in a group of hip fracture patients it was 20 ng/ml as was the case in an unselected large cohort of subjects seeking advice on osteoporosis [11, 46, 47]. Admittedly, there is a small further decline in serum PTH between 20 and 30 ng/ml of 25-(OH)D, but its relevance in clinical practice remains to be established, at least as it relates to serum PTH levels. Therefore, we feel that 20 ng/ml cutoff is most proximate to reality. Chiu et al. [48] demonstrated that subjects with hypovitaminosis D are at higher risk of insulin resistance and metabolic syndrome. We were surprised to find that we could not show significant difference in the prevalence of vitamin D depletion between diabetic and non-diabetic patients. However, the small sample size of diabetic patients in this study could have contributed for the lack of significant difference in the prevalence of vitamin D depletion between diabetic and non-diabetic patients.

Conclusion The majority of ESRD patients with secondary hyperparathyroidism receive one active form of vitamin D, which increases serum 1,25-dihydroxyvitamin D levels. However, the level of 1,25-dihydroxyvitamin D in situ may be more important than the serum level; as suggested by the presence of the 1a-hydroxylase activity in a variety of tissues, including alveolar macrophages, skin (stratum basalis), parathyroid, pancreas, adrenal medulla and cortex, colon, cerebellum, heart and liver [49]. In fact, 25-hydroxyvitamin D has been found to be effective in the treatment of uremic hyperparathyroidism, healing fractures and subperiosteal erosions, further providing evidence of significant conversion to active metabolites even in ESRD patients [50]. Our data suggest that ESRD patients should have periodic monitoring of serum 25-hydroxyvitamin D levels and prescribed supplemental vitamin D, if hypovitaminosis D is present. One study has shown that vitamin D supplements even in low doses such as over-the-counter vitamins may be a valuable tool in the prevention and treatment of hyperparathyroidism in patients with Stages 3 and 4 CKD [51]. Further studies are needed to

Seasonal hypovitaminosis D in ESRD

assess the effect of such strategy on parathyroid function, renal bone disease and requirement for active vitamin D metabolites.

Acknowledgments We wish to thank our patients for participating in the study and Ms. N. Parikh for measurement of PTH, and vitamin D metabolites. This study was presented in part in abstract format at the annual meeting of American Society of Nephrology, 1999.

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